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ANKRD9 is associated with tumor suppression as a substrate receptor subunit of ubiquitin ligase
Lee, Yejin,Lim, Byungho,Lee, Seon Woo,Lee, Woo Rin,Kim, Yong-In,Kim, Minhyeok,Ju, Hyoungseok,Kim, Mi Young,Kang, Suk-Jo,Song, Ji-Joon,Lee, J. Eugene,Kang, Changwon Elsevier 2018 Biochimica et biophysica acta. Molecular basis of Vol.1864 No.10
<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Human <I>ANKRD9</I> (ankyrin repeat domain 9) expression is altered in some cancers.</P> <P><B>Methods</B></P> <P>We tested genetic association of ANKRD9 with gastric cancer susceptibility and examined functional association of ANKRD9 with altered proliferation of MKN45 gastric cancer cells. We then identified ANKRD9-binding partners in HEK 293 embryonic kidney cells using quantitative proteomics, western blotting and complex reconstitution assays. We finally demonstrated ANKRD9's role of recognizing substrates for ubiquitination using in vitro ubiquitylation assay.</P> <P><B>Results</B></P> <P> <I>ANKRD9</I> is associated with cancer susceptibility in a comparison of single-nucleotide polymorphisms between 1092 gastric cancer patients and 1206 healthy controls. ANKRD9 depletion accelerates tumor progression by increasing cellular proliferation, piling up, and anchorage-independent growth of MKN45 cells. We discovered that ANKRD9 is a ubiquitin ligase substrate receptor subunit and has an anti-proliferative activity. ANKRD9 associates with CUL5 (not CUL2), ELOB, ELOC, and presumably RNF7 subunits, which together assemble into a cullin-RING superfamily E3 ligase complex. ANKRD9 belongs to the ASB family of proteins, which are characterized by the presence of ankyrin repeats and a SOCS box. In addition to its interactions with the other E3 ligase subunits, ANKRD9 interacts with two isoforms of inosine monophosphate dehydrogenase (IMPDH). These IMPDH isoforms are cognate substrates of the ANKRD9-containing E3 enzyme, which ubiquitinates them for proteasomal degradation. Their ubiquitination and turnover require the presence of ANKRD9.</P> <P><B>Conclusion</B></P> <P>ANKRD9, a previously unidentified E3 substrate receptor subunit, functions in tumor suppression by recognizing the oncoprotein IMPDH isoforms for E3 ubiquitination and proteasomal degradation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Human <I>ANKRD9</I> is genetically associated with gastric cancer susceptibility. </LI> <LI> ANKRD9 protein activity is functionally associated with tumor suppression. </LI> <LI> ANKRD9 is a substrate receptor subunit of CUL5-based ubiquitin ligase E3 complex. </LI> <LI> E3 with ANKRD9 ubiquitinates substrate proteins for proteasomal degradation. </LI> <LI> Two isoforms of oncoprotein IMP dehydrogenase are cognate substrates of ANKRD9. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
( Yejin Lee ),( Youlim Kim ),( Chin Kook Rhee ),( Yong Il Hwang ),( Kwang Ha Yoo ),( So Eun Lee ),( Doik Lee ),( Yong Bum Park ) 대한결핵 및 호흡기학회 2021 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.129 No.-
Introduction The most important drug in the treatment of COPD is bronchodilator, and the use of ICS is recommended only in specific condition. However, ICS/LABA continues to be widely prescribed in real practice. We aimed to compare the escalation time to open triple combination therapy from initiation of LAMA vs. ICS/LABA in COPD management in a nationwide real-world setting. Methods Patients who received COPD medication, either LAMA or ICS/LABA, with a diagnostic code of COPD, were selected from the National Health Insurance Service (NHIS) from January 2005 to April 2015. The index date was defined as the first prescription date of LAMA or ICS/LABA with COPD diagnosis during the selection period. Triple combination therapy initiation was defined as claims matched with the same prescription issued on the same date. We excluded patients who had been represcribed with triple therapy within 30 days after the index date. We also investigated the risk factors for triple therapy in crude populations and after propensity score (PS) matching of age, sex, income level, history of asthma, history of pneumonia, history of COPD exacerbation and comorbidity. Results After PS-matching, 2,444 patients were allocated in each LAMA and ICS/LABA group. We assessed the incidence rate of triple combination therapy in LAMA vs. ICS/LABA, where the Results were 81.0 and 139.8 respectively (p <0.001). The escalation time to triple therapy was 281 days in the LAMA group and 207 days in the ICS/LABA group (p=0.03). Compared to LAMA, treatment with ICS/LABA showed a higher risk of triple therapy (HR 1.601, 95% CI [1.402-1.829] (p<0.001)). Male sex was also a risk factor associated with triple therapy (HR [95% CI] 1.564 [1.352-1.809]). Conclusions This analysis shows that the initiation of LAMA therapy was related to a reduced rate of escalation to triple therapy compared to the initiation of ICS/LABA.
Clinical Significance of Bronchodilator Response (BD) in COPD
( Yejin Lee ),( Youlim Kim ),( Hyun Lee ),( Soojie Chung ),( Hayoung Choi ),( Chang Youl Lee ),( Yong Il Hwang ),( Seung Hun Jang ),( Yong Bum Park ) 대한결핵 및 호흡기학회 2020 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.128 No.-
Background Clinical significance and characteristics of COPD patients with bronchodilator response (BD) has not been characterized rigorously in previous researches. We aim to investigate whether there is difference with characteristics and exacerbation rate in patients with BD among COPD patients. Methods We performed retrospective comparative analysis of clinical characteristics, moderate and severe exacerbation rate in COPD patients who completed the lung function at least three times with either BD positive or negative. In total, 319 patients (33.5% with BD positive and 66.5% with BD negative) were included in the analysis. Results Compared with BD negative patients, there was no significant difference with age, sex, smoking status, and comorbidity in those with BD positive. Mean FEV1(L) (1.5 ± 0.5) were significantly lower in patients with BD positive than those (1.7 ± 0.7) of BD negative patients. There was no difference with eosinophil count, medication possesion ratio, and inhaler choice except long acting beta agonist. Both moderate and severe exacerbation rate ( 0.05 and 0.06, respectively) and of BD (+) was almost 50% lower than those (0.11 and 0.11, respectively) in the BD negative patients. Conclusion We found that both moderate and severe exacerbation rate was significantly lower in patients with BD positive COPD patients compared with those in BD negative COPD patients.
Noma-like necrotizing stomatitis in a child with Crohn`s disease
( Yejin Lee ),( Ik Jun Moon ),( Woo Jin Lee ),( Chong Hyun Won ),( Sung Eun Chang ),( Mi Woo Lee ),( Jee Ho Choi ),( Ki Chan Moon ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.1
Noma is known to be an opportunistic infection characterized by a devastating gangrenous stomatitis leading to severe tissue destruction. It is associated with high mortality and grotesque disfigurement of the affected area, usually the lips. According to the literature, noma predominantly affects malnourished children in sub-Saharan Africa. Only few cases have been reported in immune compromised patients from developed countries. We present an unusual case of noma-like necrotizing stomatitis in a previously healthy child with Crohn’s disease in Korea. A 11 year-old girl with rapidly progressive necrotic stomatitis of the lower lip was first diagnosed as pyoderma gangrenosum accompanying Crohn’s disease. Steroid pulse therapy was administered to control disease activity which unexpectedly resulted in aggravation of the lesion. Eventually the diagnosis of noma-like necrotizing stomatitis was made. After cessation of systemic steroid and administration broad spectrum antibiotics with intravenous immunoglobulin, the disease slowly improved over a month. However, as the fibrous tissue replaced the whole lips, the patient was left with speech impairment due to buccal stricture and disfigurement. We report this case to increase clinicians’ awareness of the disease and to stress the importance of early recognition and management of this rare disease in order to minimize sequelae.
이예진 ( Yejin Lee ),이찬욱 ( Chanwook Lee ),이슬비 ( Seulbi Lee ),현병근 ( Bynggeun Hyun ),송요성 ( Yosung Song ),김양민 ( Yangmin X. Kim ),조송래 ( Songrae Cho ) 한국환경농학회 2021 한국환경농학회 학술대회집 Vol.2021 No.-
농업의 공익기능 증진을 위한 공익직불제 시행으로 농업인의 적정 비료사용이 의무화되었다. 농업기술센터에서는 농업인에게 적정 비료사용량을 처방하기 위해 흙토람 비료사용처방 프로그램을 통해 비료사용처방서를 발급하고 있으나, 아직 비료사용기준이 설정되지 않은 소면적 재배 작물은 적정 비료사용량을 처방하기 어려운 실정이다. 본 연구에서는 농업인의 처방 수요가 있으나 아직 비료사용기준이 설정되지 않은 소면적 작물의 농가 현장 비료사용량과 토양 화학성을 조사하였고, 작물의 양분흡수량을 분석하였다. 대상작물은 애플수박, 복수박, 단호박, 아로니아이며, 조사 지역은 재배농가가 많은 지역으로 선정하였다. 애플수박은 경남 합천, 전북 고창, 충남 예산에서 총 20농가, 복수박은 전남 광양에서 15농가, 단호박은 경남 하동, 충남 천안에서 총 22농가, 아로니아는 충북 단양, 영동, 옥천에서 총 24농가에 대해 조사하였다. 애플수박과 복수박은 시설 재배지, 단호박과 아로니아는 노지 재배지에서 조사하였다. 애플수박과 복수박 재배지의 평균 비료사용량은 각각 질소-인산-칼리=15.6-7.1-7.8 kg/10a, 24.0-12.6-10.2 kg/10a 이었으며, 애플수박에 비해 비료 사용량이 많았던 복수박 재배지의 유효인산과 질산태질소의 함량이 높았다. 애플수박과 복수박의 평균 양분흡수량은 각각 질소 9.4, 7.5 kg/10a로 애플수박의 질소 흡수량이 많아 농가에서 질소 비료사용량을 줄일 필요가 있다고 판단되었다. 단호박 재배지의 평균 비료사용량은 질소-인산-칼리=16.0-9.7-9.3 kg/10a이었으며, 단호박의 평균 양분흡수량은 질소 8.7 kg/10a 이었다. 단호박은 1주에 과 1개씩 수확하기 때문에 연속적으로 수확하는 호박 질소 흡수량의 약 1/3 수준이었다. 아로니아의 평균 비료사용량은 질소-인산-칼리=18.8-7.0-8.1 kg/10a이었으며, 과의 평균 질소 흡수량은 1.9 kg/10a 이었다. 한 나무 당 잎의 질소 흡수량은 작물 특성상 구하기 어려워 산정이 어려우나, 잎의 질소 함량은 평균 2.6%, 과는 1.0%로 잎에서 흡수량이 많았음을 추정할 수 있었다. 조사결과를 통해 농가에서 작물 흡수량에 비해 과다하게 비료를 주는 작물은 비료 사용량을 줄여 줄 필요가 있다고 판단되었다. 작물의 농가 비료사용량과 토양 화학성, 양분흡수량을 기초자료로 활용하여 농가에 적정량의 비료를 추천할 수 있는 기준을 설정할 계획이다.